**2. Autonomic nervous system regulation of cardiovascular functions**

Autonomic nervous system (ANS), a portion of peripheral nervous system, has two subdivisions viz. sympathetic and parasympathetic nervous system. They are responsible for regulating the functions of almost organs of the body via visceral reflexes. Centrally, ANS activities or reflexes are integrated and controlled by hypothalamus, brain stem and spinal cord. Heart and blood vessels are innervated by sympathetic and parasympathetic nerve fibers. Thus, their functions are largely regulated by ANS apart from other regulating factors to adapt to different shortterm or long-term physiological/pathological changes of the internal environment of the body.

#### **2.1 Regulation of cardiac functions**

The main function of the heart is to pump blood into the closed circuit of circulation. The efficiency of this mechanical property of the heart depends on normal electrophysiology of the heart which per se depends on normal structural and functional integrity of sinus atrial node (SA node) and rest of the conducting system of the hear t. Autonomic nervous system plays crucial role in controlling both electrical and mechanical properties of the heart. However, the degree of influence of sympathetic and parasympathetic nerves on heart functions depends on their abundance of innervation in different parts of the heart.

Sympathetic nervous system via right and left cardiac nerves innervate atria and ventricles (including conducting system). Right cardiac nerve predominantly innervates SA node and it has more influence on heart rate (HR) and on the other hand left cardiac nerve predominantly controls myocardial contractility. Thus, the net effect of sympathetic stimulation is to increase HR, conduction velocity and strength of myocardial contractility. Parasympathetic nervous system through right and left vagus nerves innervate predominantly atrial muscle and very sparsely ventricular myocardium. Right vagus nerve primarily innervates the SA node and left vagus nerve innervates mainly atrio-ventricular node (AV node). Thus, the net effect of parasympathetic stimulation is to decrease HR and slightly decrease strength of heart contractility. Dynamic interaction occurs between sympathetic

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*Type 2 Diabetes Mellitus: Cardiovascular Autonomic Neuropathy and Heart Rate Variability*

and parasympathetic divisions. However, during rest, parasympathetic tone predominates over sympathetic tone. Therefore, resting HR is mainly controlled by the vagal nerve tone [15]. Hence, resting HR is a marker of vagal nerve function

Arteries and veins are innervated only by sympathetic nerve fibers, whereas, capillaries do not have any autonomic nerve innervation. Thus, vasomotor tone of almost all blood vessels is mainly determined by sympathetic tone. Sympathetic stimulation causes vasoconstriction and vice versa. Parasympathetic nerve fibers do innervate some blood vessels of salivary glands, gastrointestinal glands and genital

DAN is quite common, yet remained mostly undiagnosed and micro-vascular complications of T2DM are affecting many organ systems (gastrointestinal, genitourinary, cardiovascular) of the body [7]. However, CAN is clinically the most important form of DAN as it is associated with life-threatening complications (arrhythmias, silent MI) and sudden death [9]. The underlying pathophysiology of DAN is still unclear; however, it has been attributed to chronic hyperglycemia induced oxidative stress and inflammation with subsequent neuronal injury and

Oxidative stress and inflammation are interlinked, as one causes another and vice versa, and they occur even under normal physiological conditions. However, these two phenomena last for a brief period as they are suppressed by intrinsic negative feedback mechanisms; increased production of antioxidants and antiinflammatory cytokines [19]. But, in certain chronic diseases like T2DM these altered states of internal environment sustain for a prolonged period as positive feedback mechanisms overrides the negative feedback mechanisms [19]. In addition, reduced parasympathetic nerve function due to autonomic dysfunction in T2DM leads to chains of inflammatory responses [20]. Thus, oxidative stress and inflammation are very prominent features in T2DM linked to both microvascular and macrovascular complications associated with T2DM [19]. Certain cells are particularly susceptible to hyperglycemic induced injury as their intracellular glucose concentration increases in a linear fashion with respect to the extracellular glucose level [16]. This is especially true for endothelial cells and neurons as the transport of glucose through their cell membranes is mediated by insulin-

Hyperglycemia induces overproduction of mitochondrial superoxide in endothelial cells of large and small blood vessels and neuronal axons [9, 16]. This leads to intracellular accumulation of reactive oxygen species (ROS) with subsequent activation of five major metabolic pathways: polyol pathway flux, increased formation of advanced glycation end-products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C (PKC) isoforms, and overactivity of the hexosamine pathway [9, 16]. Over activity of these five metabolic pathways leads to accumulation of toxic metabolic derivatives and pro-inflammatory substances, bringing about following consequences: vascular

**3.1 Hyperglycemia induced oxidative stress and inflammation**

*DOI: http://dx.doi.org/10.5772/intechopen.95515*

**2.2 Regulation of vascular functions**

**3. Diabetic autonomic neuropathy**

status [15].

erectile tissues.

death [9, 16–19].

independent GLUTs [16].

#### *Type 2 Diabetes Mellitus: Cardiovascular Autonomic Neuropathy and Heart Rate Variability DOI: http://dx.doi.org/10.5772/intechopen.95515*

and parasympathetic divisions. However, during rest, parasympathetic tone predominates over sympathetic tone. Therefore, resting HR is mainly controlled by the vagal nerve tone [15]. Hence, resting HR is a marker of vagal nerve function status [15].
